Hypothesis testing: is clozapine's superior efficacy dependent on moderate D2 receptor occupancy?
BACKGROUND
How clozapine exerts superior antipsychotic efficacy in treatment-resistant schizophrenia is not known. Moderate (rather than "full") occupancy of D2 postsynaptic receptors may be crucial, perhaps by achieving a more effective D1/D2 or serotonin-2a/D2 ratio. The objective of this study was to test the moderate occupancy hypothesis of clozapine's superior efficacy.


METHODS
Data from the New York effectiveness of clozapine study were used to compare 6-week clozapine treatment results in patients discontinuing oral neuroleptic medication with similar patients discontinuing long-acting depot neuroleptic. The latter group is assured "full" D2 occupancy during the 6-week clozapine treatment.


RESULTS
If moderate occupancy is crucial for superior efficacy, the oral discontinuation group should manifest more improvement. Both groups showed the 6-week improvement expected with clozapine therapeutics [31% and 29% reduction in Brief Psychiatric Rating Scale (BPRS) scores in the depot and oral groups, respectively]. An analysis of covariance (for baseline BPRS) revealed no difference in change scores (df = 1,100; F = 0.17; p = ns).


CONCLUSIONS
The reduced D2 occupancy hypothesis is rejected.
Carpenter
W T
WT
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore 21228, USA.
Zito
J M
JM
Vitrai
J
J
Volavka
J
J
D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003024:Clozapine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D006801:Humans; D011569:Psychiatric Status Rating Scales; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism*
D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D003024:Clozapine